Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial

Abstract

This prospective, multicenter, phase II study investigated the use of four cycles of bortezomib-dexamethasone induction treatment, followed by high-dose melphalan and autologous stem cell transplantation (SCT) in patients with newly diagnosed light chain amyloidosis. The aim of the study was to improve the hematologic complete remission (CR) rate 6 months after SCT from 30% to 50%. Fifty patients were enrolled and 72% had two or more organs involved. The overall hematologic response rate after induction treatment was 80% including 20% CR and 38% very good partial remissions (VGPR). Fifteen patients did not proceed to SCT for various reasons but mostly treatment-related toxicity and disease-related organ damage and death (2 patients). Thirty-one patients received melphalan 200 mg/m2 and four patients a reduced dose because of renal function impairment. There were no deaths related to the transplantation procedure. Hematologic responses improved at 6 months after SCT to 86% with 46% CR and 26% VGPR. However, due to the high treatment discontinuation rate before transplantation the primary endpoint of the study was not met and the CR rate in the intention-to-treat analysis was 32%. Organ responses continued to improve after SCT. We confirm the high efficacy of bortezomib-dexamethasone treatment in patients with AL amyloidosis. However, because of both treatment-related toxicity and disease characteristics, 30% of the patients could not proceed to SCT after induction treatment. (Trial registered at Dutch Trial Register identifier NTR3220).

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA

“…At this time, the most commonly used front-line regimens for this disease are CyBorD, 7 melphalan with dexamethasone, 52 and high-dose melphalan (HDM) with ASCT, although the latter is not feasible for many patients with AL amyloidosis. [9][10][11] In patients with newly diagnosed AL amyloidosis receiving CyBorD, 7 melphalan with dexamethasone, 52 and HDM with ASCT, [9][10][11] hematologic CR rates were 23%, 12%, and 34% to 48%, respectively. DARA SC plus CyBorD achieved a stringent dFLC response in 68% of patients compared with 30% with bortezomib-based combinations (95% received CyBorD).…”

“…7,8 Similar or higher CR rates are achievable with high-dose melphalan treatment and autologous stem cell transplant (ASCT), but this therapy is only feasible in a minority of patients. [9][10][11] In addition, patients with AL amyloidosis experience more frequent and severe toxicity compared with patients with MM receiving the same regimens. 12,13 Thus, an unmet need remains for more tolerable and effective therapies for AL amyloidosis.…”

Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis

“…Importantly, VGPR/CR rate was comparable to that observed (50%) in the HOVON-104 trial with bortezomib induction and ASCT, and the duration of response was similar to that reported by the Boston University group for ASCT (median, 4.3 years). 12,18 A single treatment-related death occurred during CyBorD treatment. This indicates that careful biomarker-based selection of transplant candidates and sequential therapy that limits treatment intensity based on the quality of response dramatically reduces early mortality.…”

“…10 This latter approach can result in deeper hematologic responses (HRs) and longer survival than ASCT alone and has been studied in recent trials. [11][12][13] In particular, bortezomib-based induction can result in deep HRs and organ improvement, considered a satisfactory end point in AL amyloidosis, before ASCT. 7,14 At our center, transplant-eligible patients are treated upfront with cyclophosphamide/bortezomib/ dexamethasone (CyBorD) and they proceed to ASCT only in case of an unsatisfactory response.…”

High-Dose Melphalan and Autologous Peripheral Blood Stem Cell Transplantation in AL Amyloidosis

“…However, this trial was critiqued for the use of non-contemporary induction regimen. Induction therapy with novel agents prior to HDM/SCT, specifically bortezomib and dexamethasone, has been studied in multiple clinical trials showing higher hematologic response rates, organ responses, and OS [14-16]. Nevertheless, induction therapy should be used with caution of not delaying more definitive treatment, as 14–35% of patients would not proceed to SCT after induction due to clinical deterioration of organ function making them ineligible to undergo SCT.…”